TY - JOUR
T1 - Pharmacodynamic properties of methotrexate and Aminotrexate™ during weekly therapy
AU - Cole, Peter D.
AU - Alcaraz, María José
AU - Smith, Angela K.
AU - Tan, John
AU - Kamen, Barton A.
N1 - Funding Information:
Acknowledgments PDC is a Damon Runyon-Lilly Clinical Investigator, supported in part by the Damon Runyon Cancer Research Foundation (CI ·16-03). BAK is an American Cancer Society Professor. This work was supported in part by an FDA Orphan Products Development grant (FD-R-001832-03) and by the Institute for Children with Cancer and Blood Disorders, New Brunswick, NJ.
Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.
PY - 2006/6
Y1 - 2006/6
N2 - 4-amino-pteroyl-glutamic acid (Aminotrexate™; AMT) has several advantages over the related antifolate methotrexate (MTX), including greater potency, complete oral bioavailability, and greater accumulation by leukemic blasts in vitro. We compared the pharmacodynamic properties of AMT (given orally at 4 mg/m2 in two divided doses per week) and MTX (100 mg/m 2 in four divided doses per week) among children with acute lymphoblastic leukemia. We find AMT and MTX to have equivalent penetration into the bone marrow compartment of these patients, as indicated by the steady-state concentrations within mature red blood cells (RBCs). However, MTX concentrations in the cerebrospinal fluid after oral dosage are significantly greater than AMT. To confirm these clinical observations, mice were treated four weekly injectons of AMT or MTX, at a 1:20 dosage ratio, and tissue antifolate content was then determined over the subsequent 22 days. We confirm the selective exclusion of AMT from the CNS compartment, while showing equivalent accumulation of AMT and MTX in the RBCs, liver, spleen, kidneys and testes. Finally, we demonstrate that AMT, MTX, and their predominant polyglutamate species are equipotent inhibitors of their target intracellular enzyme dihydrofolate reductase, emphasizing the critical nature of steady-state tissue accumulation in determining the relative cytotoxic potency of these two antifolates.
AB - 4-amino-pteroyl-glutamic acid (Aminotrexate™; AMT) has several advantages over the related antifolate methotrexate (MTX), including greater potency, complete oral bioavailability, and greater accumulation by leukemic blasts in vitro. We compared the pharmacodynamic properties of AMT (given orally at 4 mg/m2 in two divided doses per week) and MTX (100 mg/m 2 in four divided doses per week) among children with acute lymphoblastic leukemia. We find AMT and MTX to have equivalent penetration into the bone marrow compartment of these patients, as indicated by the steady-state concentrations within mature red blood cells (RBCs). However, MTX concentrations in the cerebrospinal fluid after oral dosage are significantly greater than AMT. To confirm these clinical observations, mice were treated four weekly injectons of AMT or MTX, at a 1:20 dosage ratio, and tissue antifolate content was then determined over the subsequent 22 days. We confirm the selective exclusion of AMT from the CNS compartment, while showing equivalent accumulation of AMT and MTX in the RBCs, liver, spleen, kidneys and testes. Finally, we demonstrate that AMT, MTX, and their predominant polyglutamate species are equipotent inhibitors of their target intracellular enzyme dihydrofolate reductase, emphasizing the critical nature of steady-state tissue accumulation in determining the relative cytotoxic potency of these two antifolates.
KW - Acute lymphoblastic leukemia
KW - Aminopterin
KW - Methotrexate
KW - Neurotoxicity
KW - Polyglutamates
KW - Rheumatoid arthritis
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U2 - 10.1007/s00280-005-0115-3
DO - 10.1007/s00280-005-0115-3
M3 - Article
C2 - 16170572
AN - SCOPUS:33645750806
SN - 0344-5704
VL - 57
SP - 826
EP - 834
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 6
ER -